Tiagabine: efficacy and safety in adjunctive treatment of partial seizures.

PURPOSE: To assess the efficacy and safety of tiagabine (TGB), a new antiepileptic drug (AED), as add-on therapy in patients with refractory partial seizures. METHODS: This response-dependent study used an open-label screening phase (in which patients were titrated to their optimal TGB dose, < or =64 mg/day) followed by a double-blind, placebo-controlled, crossover phase. Initial eligibility criteria included (a) seizures inadequately controlled by existing AEDs, and (b) six or more partial seizures during an 8-week baseline period. Patients showing benefit from TGB (> or =25% reduction in total seizure rate relative to baseline) were eligible for randomization into the double-blind phase, which comprised two 7-week assessment periods separated by a 3-week crossover period. RESULTS: Forty-four (50%) of the 88 enrolled patients entered the double-blind phase of the study during which there were significant reductions compared with placebo in all partial (p < 0.01), complex partial (p < 0.001), and secondarily generalized tonic-clonic seizure rates (p < 0.05). Thirty-three percent of patients experienced a reduction of > or =50% in the all partial seizure rate. Eight (22%) patients receiving TGB during the double-blind phase reported adverse events, of which dizziness and incoordination were the most frequent. Three patients withdrew from treatment during the double-blind phase because of adverse events; two during treatment with TGB and one during treatment with placebo. TGB did not affect plasma concentrations of other coadministered AEDs. CONCLUSIONS: TGB was significantly better than placebo in terms of seizure rate reduction and was generally well-tolerated in patients with difficult to control seizures.

The influence of roughness, angle, range, and transducer type on the echo signal from planar interfaces.

The received electrical echo signal from a pulse-echo system insonifying a planar interface was measured for varying degrees of rms roughness [0 to 0.29 mm (0 to 1.7 lambda)], angles of incidence, theta, (-7 degrees to 7 degrees), and ranges to a planar or focused transducer. The effect of varying theta is quantified in terms of the energy of the received signal, E(theta), and the normalized spectrum of the received signal. E(theta) is approximately Gaussian when using a planar transducer or a focused transducer with the reflecting interface located at or beyond the focal point. For focused transducers with the interface located closer than the geometrical point of focus, two maxima can sometimes be observed when varying the incident angle. As is generally known, the width of E(theta) is strongly dependent on transducer type, e.g., for a smooth interface, the -3 dB width for a 25.4 mm diameter 5-MHz planar and focused transducer was approximately 0.5 degree and 4 degrees (at the focal point), respectively. E(0 degree) as a function of surface roughness, Rq, was nearly linear on a decibel scale, with a slope of -109 dB/(Rq/lambda) and -61 dB/(Rq/lambda) for planar and focused transducers, respectively. The characteristic nulls present in the normalized spectra of the echo signal at non-normal incidence tend to vanish with increasing Rq when using planar transducers. For focused transducers, the normalized spectra change from relatively flat to monotonically decreasing as Rq increases, and they exhibit reduced amplitude with increased incident angle.

Application of time delay spectrometry for rough surface characterization.

This paper describes the design and performance of an ultrasound measurement system, utilizing a swept frequency excitation signal, for analyzing the backscattered signal from planar rough surfaces. The implementation is in the form of a time delay spectrometry (TDS) system operating in reflection mode whose advantages are improved signal-to-noise ratio even with low peak power relative to conventional pulse-echo methods. Because of simultaneous transmission and reception, the TDS system requires two transducers. The TDS measurement system uses a swept frequency spectrum analyzer as the central analog processing unit. Both planar piston and focused transducers in the low MHz range were used for the measurements. Due to the statistical nature of rough surface backscatter, the mean of several statistically uncorrelated measurements is required to characterize the scattering behavior of a given rough surface. Backscatter data are obtained for a series of planar rough surfaces, in the form of scattering magnitude vs. frequency and vs. incident (=backscattered) angle. Analysis of the results reveals a good correlation between the root-mean-square (RMS) height and mean backscatter magnitude at 0 degrees incident angle, and between the ratio of RMS height to correlation length and the difference in mean backscatter magnitude between 0 degrees and 5 degrees.

Pharmacokinetics of levormeloxifene in young versus elderly postmenopausal women.

BACKGROUND: Physiologic changes of aging may affect processes of drug absorption and distribution, in some cases necessitating age-dependent dose adjustment. OBJECTIVE: The possibility of age dependence in the pharmacokinetic behavior and tolerability of levormeloxifene was investigated in a single-center, open-label study. METHODS: The study comprised 2 groups of healthy postmenopausal women: group A included younger subjects (50-60 years) and group B included elderly subjects (> or = 66 years). All subjects received a single 40-mg tablet of levormeloxifene base. Blood samples were collected immediately before drug intake and at several points after administration, through day 34. Peak plasma concentration, time to maximum plasma concentration, area under the plasma concentration-time curves from zero to the last quantifiable value and to infinity, and terminal half-life were calculated for levormeloxifene and compared between age groups. RESULTS: Of 29 subjects enrolled, 28 (15 group A, 13 group B) completed the study. The ages of the women in group A ranged from 50 to 58 years and in group B from 66 to 79 years. No serious adverse events were reported. Ten subjects experienced 17 adverse events, of which 2 (abdominal pain and vaginal hemorrhage) were judged to be possibly related to study drug. There was no noticeable difference between age groups in the frequency of adverse events or laboratory abnormalities. The plasma concentration-time curves of levormeloxifene were indistinguishable between age groups up to 48 hours after dosing. From 72 hours onward, the mean plasma concentration-time curve was approximately 20% higher and the area under the curve was approximately 19% greater in the older subjects compared with the younger subjects. However, no statistically significant differences were observed between groups in any of the pharmacokinetic parameters, except for the elimination rate constant. The difference in mean elimination half-life was 25 hours (group A, 126 hours; group B, 151 hours). CONCLUSION: The findings suggest that it is not necessary to adjust the dose of levormeloxifene on the basis of age in postmenopausal women. However, these results need confirmation in a multiple-dose setting under steady-state conditions--that is, as the drug is intended to be used clinically.

Statistics of the integrated backscatter estimate from a blood-mimicking fluid.

This work evaluates the variance of the integrated backscatter (IBS) from moving blood [or blood-mimicking fluid (bmf)] as a way of determining the quality of the mean IBS estimate. The main motivation for this work comes from the fact that absolute IBS values from tissues adjacent to arterial blood can be found by normalizing the measured backscatter energy with the IBS of moving, deaggregated blood. The paper describes the parameters that control the statistics of the IBS estimate, which is calculated for the stochastic ultrasound backscatter signals from flowing blood. It further formulates how the measurement parameters should be specified so that an appropriately low blood IBS variance is ensured or, alternatively, a specified accuracy of the tissue IBS estimate is obtained. First, the paper provides an analytic formulation of the statistics of the IBS, based on a sequence of sampled echoes from a nonstationary Gaussian scattering medium. The analysis incorporates the correlation between the sample values as well as the correlation between the IBS of the individual echoes. The estimate of the mean IBS has been shown to be chi-squared distributed with a determinable order. With the degree of correlation between the samples and between the IBS of individual echoes specified, the number of measurements required to obtain an IBS estimate with a specified variance is readily calculated. Next, a sequence of synthetic echoes is produced and arranged as columns in a data matrix. The echoes are generated such that the second-order statistics along the rows and columns of the matrix match that of actually observed echoes. The actual variance of the mean IBS estimate for the synthetic echoes is calculated and compared with the variance determined from the analytic model, and a good agreement has been found. Finally, sequences of actual backscattered echoes from circulating blood-mimicking fluid are acquired and analyzed to determine the variance of their mean IBS estimate. Based on the measured second-order statistics of the rows and columns of the data matrix for the actual echoes, the observed variance of the mean IBS estimate was compared with the analytically determined variance and with good agreement. Thus, the paper has shown through modeling, simulations, and experiments how the variance of the IBS estimate of the blood backscatter signal can be quantified and reduced to a specified tolerable level.

Population pharmacokinetics of tiagabine in epileptic patients on monotherapy.

A retrospective study of the population pharmacokinetics of tiagabine was performed from sparse data collected in a multicentre clinical trial in patients with newly diagnosed partial seizures. The purpose was to estimate the inter patient variability and to study the influence of various demographic, environmental and pathophysiological parameters on the pharmacokinetics of tiagabine in patients on monotherapy. A total of 593 plasma concentrations from 130 patients dosed with 2.5, 5, 7.5 or 10 mg tiagabine twice daily were used for modelling. A one-compartment open model with first-order absorption and elimination was fitted to the concentration-time data using the NONMEM program. Selection of covariates was initially performed using stepwise linear regression analyses. The selected covariates were incorporated in the population model and the importance of each covariate was investigated by means of backwards elimination. A one-compartment model with first-order absorption and elimination adequately described the tiagabine concentration-time profile. The apparent clearance as well as the apparent volume of distribution were both significantly correlated to body height in a nonlinear relationship. No other demographic, environmental or clinical chemical parameters were identified as covariates although only a few pathological values of the latter were present in the data. The mean values of CL/f was 6.10 l/h, of V/f was 62.0 l and of k(a) was 1.25 h(-1) for a subject of 170-cm height. The population half-life was 5.72 h. The apparent clearance and volume of distribution of tiagabine in epilepsy patients on monotherapy were both dependent on body height. Prospective studies are required in order to reveal if dose adjustments based on body height will result in improved therapeutic outcome.

Tiagabine, a novel antiepileptic agent: lack of pharmacokinetic interaction with digoxin.

OBJECTIVE: To assess the possibility of any clinically relevant pharmacokinetic interactions between tiagabine, a novel antiepileptic drug, and digoxin. METHODS: Potential pharmacokinetic interactions between tiagabine and digoxin were investigated in an open-label, two-period cross-over study in healthy male volunteers. Thirteen volunteers, aged between 18 and 43 years, were randomised to receive digoxin (0.5 mg twice a day for 1 day, then 0.25 mg once a day for 8 days) either alone or co-administered with tiagabine (4 mg three times daily for 9 days). Following a 7-day washout period, volunteers crossed over to the other dosing regimen. Peak serum concentration, time to maximum serum, concentration, area under the serum concentration-time curve from zero to 24 h and steady state serum concentration were calculated for digoxin and compared between treatment groups. RESULTS: No statistically significant differences between treatment groups were observed for any of the derived digoxin pharmacokinetic parameters. The most common adverse events reported during digoxin alone and in combination with tiagabine were somnolence and headache; an overall greater frequency of adverse events was reported during combined treatment. Adverse events were generally mild in nature; no serious adverse events were reported. CONCLUSIONS: At the doses administered, there is no evidence of a pharmacokinetic interaction between digoxin and tiagabine in healthy male volunteers.

Absence of interaction between tiagabine, a new antiepileptic drug, and the benzodiazepine triazolam.

In a randomised, double blind, placebo-controlled, four-period cross-over study in 12 healthy volunteers, the potential pharmacodynamic and pharmacokinetic interactions between the new antiepileptic drug, tiagabine, and the benzodiazepine, triazolam, were investigated. A single dose of tiagabine HCl 10 mg did not enhance the sedative or cognitive effects of a single dose of the benzodiazepine triazolam 0.125 mg, although the time-course of the effects was prolonged. Furthermore, tiagabine did not produce any statistically significant effects on the pharmacokinetics of triazolam. Similarly, the pharmacokinetics of tiagabine were not modified by triazolam. Tiagabine was well tolerated when administered alone or with triazolam.

The diffraction response interpolation method.

Computer modeling of the output voltage in a pulse-echo system is computationally very demanding, particularly when considering reflector surfaces of arbitrary geometry. A new, efficient computational tool, the diffraction response interpolation method (DRIM), for modeling of reflectors in a fluid medium, is presented. The DRIM is based on the velocity potential impulse response method, adapted to pulse-echo applications by the use of acoustical reciprocity. Specifically, the DRIM operates by dividing the reflector surface into planar elements, finding the diffraction response at the corners of the elements, calculating the response integrated over the surface element by time-domain convolutions with analytically determined filters, and summing the responses from the individual surface elements. As the method is based on linearity, effects such as shadowing, higher-order diffraction, nonlinear propagation, cannot be directly incorporated in the modeling. The DRIM has been compared to other modeling tools when possible. Excellent agreement between the results obtained with the DRIM and the alternative techniques have been found, and the DRIM offers reductions in computation time in the range from 30 to 400 times. Experimental results obtained using a planar circular transducer together with cylindrical reflectors were compared to DRIM results and fairly good agreement was observed.

Ultrasonic measurement of forced diameter variations in an elastic tube.

This paper presents an ultrasonic measurement technique to determine an elasticity parameter, called the apparent compliance, in a thin-walled tube. The apparent compliance is obtained by ultrasound pulse-echo measurement of the diameter variation in response to an externally applied time-varying pressure function. Specifically, the diameter variation is obtained by tracking the time shift of the echoes from the front and back walls of the tube using a correlation technique. This technique is named the Forced Vibration Method (FVM). This approach to compliance measurement is distinctly different from compliance measurements using the blood function as excitation function, but is closely related to the elastic imaging concept. Two experimental models, termed the rigid wall model and the leg-like model, have been developed. These models allow the amplitude and frequency of the pressure function as well as the dimensions and properties of the tube to be varied. Results for the diameter variations vs. location along the tube and frequency of external pressure function are presented for both models.

Efficient angular spectrum decomposition of acoustic sources. I. Theory.

The angular spectrum decomposition is evaluated in terms of plane wave angular range, angular resolution, and spatial aliasing error using two-dimensional FFT (2-D FFT). The algorithm makes possible the source plane decomposition of normal velocity and pressure fields radiated by transducers of arbitrary shape, with significantly faster results achievable for planar sources. Although the angular spectrum is equally applicable to fields far from the transducer, the efficient calculation is derived specifically for fields in or very close to the source plane. An antialiasing algorithm is proposed that allows the source to be discretized with fewer sample points for a given accuracy than required with simple discretization techniques. Guidelines for the selection of sampling interval, discretization size, etc. are developed on an application-specific basis and indicate the best ratio of numerical accuracy to computational cost.

Efficient angular spectrum decomposition of acoustic sources. II. Results.

For pt.I see ibid., vol.40, no.3, p.238-49 (1993). Results of angular spectrum computations are presented for three applications: general decomposition, pressure field calculation, and modeling of pulse-echo measurements. Wherever possible, analytical (exact) results are used as reference for the decomposition results. This permits the accuracy of the angular spectrum decomposition to be evaluated for specific choices of M and N where M is the number of samples across the maximum characteristic length, d, of the source region and N is the total number of samples along each side of the source decomposition plane, and for both sampling techniques. Based on the results for the three applications, guidelines for choosing M and N are presented in a graphical format.

Target velocity estimation with FM and PW echo ranging Doppler systems I. Signal analysis.

The theoretical foundation is presented for velocity estimation with a pulsed wave (PW) Doppler system transmitting linear FM signals. The Doppler system possesses echo ranging capabilities and is evaluated in the context of Doppler ultrasound for blood velocity measurement. The FM excitation signal is formulated and the received signal is derived for a single moving particle. This signal is similar to the transmitted signal, but with modified parameters due to Doppler effect and range. The demodulated received signal is subsequently derived and analyzed. It is shown that, due to the Doppler effect, this is a linear sweep signal as well. The velocity and range information obtainable from one and two consecutively received signals are described. The latter case establishes the basis for an FM Doppler system for blood velocity measurements.

Target velocity estimation with FM and PW echo ranging Doppler systems. II. Systems analysis.

For part I see ibid., vol.40, no.4, pp.366-372 (1993). In Part I, the encoding of the velocity and range information into the received and demodulated signals based on transmission of coherent repetitive linear sweep signals, was discussed. In the present work, two different implementations of FM Doppler systems that can be used to obtain velocity profiles are presented. The first implementation is similar to the implementation of a conventional pulsed wave (PW) Doppler system, based on measurement of phase shift (correlation based system): the second implementation is a frequency-domain analog to the PW Doppler system, based on time shift measurements (cross correlation-based system).

Reconstruction of the acoustical impedance profile of a multilayer medium.

The recovery of the acoustical reflectivity function and impedance profile of a layered medium from bandlimited and noisy pulse-echo ultrasonic data is considered. The effects of the transducer and the noise are reduced using Wiener filtering. With further signal processing and a priori knowledge of the attenuation and the velocity profiles, the compensated coefficients of the reflectivity function and the impedance profile are recovered. The reconstruction techniques are presented analytically, and are also evaluated in an experimental setup composed of a conventional pulse echo system, a data acquisition and a data processing system. Under experimental conditions, the RMS errors in the estimation of the compensated acoustical discrete impedance profile were within 3% of the calculated values.

Pharmacokinetics of a low molecular weight heparin, logiparin, after intravenous and subcutaneous administration to healthy volunteers.

In six healthy volunteers we have estimated the pharmacokinetic parameters of the anti factor Xa (AXa) and anti factor IIa (AIIa) activities of a LMW heparin, Logiparin. For the AXa the following parameters were estimated in a 1-compartment model (mean and 95% confidence limits in brackets): elimination half life 82 minutes (60-127 min), absorption half life (s.c. inj.) 200 minutes (137-368 min), bioavailability 90% (24-156%), and apparent volume of distribution 3.9 l (3.1-5.2 l). The plasma activity was linearly correlated to the dose given and to the body weight of the volunteer. For the AIIa the parameters estimated in a 1-compartment model were: elimination half life 71 minutes (52-115 min), absorption half life 257 minutes (133-3442 min), bioavailability 67% (44-90%), and apparent volume of distribution 10.1 l (7.2-16.7 l). The plasma activity was dependent on dose and body weight but it also seemed to be influenced by individual factors. This study shows that the absorption rate is the rate limiting factor and the explanation for the long lasting effect of this LMW heparin after subcutaneous injection. The slow absorption rate and the high bioavailability are probably the major advantages of LMW heparins compared to conventional heparin.

On the behavior of instantaneous frequency estimators implemented on Doppler flow imagers.

Analytical and experimental results have been used to examine the behavior of the "autocorrelator" or instantaneous frequency detector (IFD) applied to color-coded Doppler flow mapping. Two effects were studied. The first was the influence of noise, as modified by a stationary echo canceler, on the Doppler frequency detector. Our theoretical considerations predict that uncorrelated input noise signals become partially correlated after cancellation, and bias the response to flow signals. This effect was confirmed by experiment. The canceler introduces a constant negative bias into the denominator of the algorithm implemented by the estimator, thus changing the indicated frequency. The second phenomenon, examined through processing computer simulated Doppler signals added to real noise, is related to the possible ambiguity, called aliasing, of measurements of the mean frequency for wide-band Doppler spectra. We show that aliasing cannot be observed with these spectra unless the signal is first processed by a canceler. Thus, regions of apparent reversed flow direction on two-dimensional flow images of turbulence must usually be due to real reversal of the flow direction.

Insulin requirement in non-insulin-dependent diabetes mellitus: relation to simple tests of islet B-cell function and insulin sensitivity.

Evaluation of simple tests of islet B-cell function and insulin sensitivity as predictors of metabolic control was performed during 3 months of insulin withdrawal in 25 insulin-treated diabetic subjects. All patients had a glucagon stimulated plasma C-peptide concentration above 0.33 nmol/l and a fasting plasma C-peptide concentration above 0.20 nmol/l a few days before insulin withdrawal. Insulin sensitivity was measured as the glucose disappearance rate (k) during an intravenous insulin tolerance test. Two patients were considered insulin-requiring due to high fasting blood glucose levels (greater than 20 mmol/l) and two patients due to an increase in glycosylated haemoglobin of more than 1.1% (greater than approximately 3SD) in combination with weight loss. None of the remaining patients had a significant increase in glycosylated haemoglobin. An inverse correlation was found between stimulated C-peptide levels and insulin sensitivity (r = 0.41, p less than 0.05). Fasting and stimulated C-peptide concentrations of 0.40 and 0.70 nmol/l, respectively, separated non-insulin-requiring patients from a group consisting of both insulin- and non-insulin-requiring patients. At these C-peptide levels the predictive value of a positive test was 100% while the predictive value of a negative test was as low as 33% or 27% depending on whether fasting or stimulated C-peptide concentration was used. Including the k value in the prediction only increased the predictive values of negative tests to 40% and 33%, respectively.

The effect of low molecular weight heparin on experimental thrombosis and haemostasis--the influence of production method.

Three low molecular weight heparins prepared by enzymatic depolymerization, chemical degradation, and fractionation, respectively were studied in experimental thrombosis and haemostasis models in vivo and in biological assays in vitro. The three low molecular weight heparins, which had comparable molecular weight distributions, showed very similar activities both in vitro and in vivo. All three showed dose dependent thromboprophylactic effect. The antithrombotic effects of the low molecular weight heparins and conventional heparin administered in the same dose (30 XaI u/kg b.w.) did not differ. Neither LMW heparin nor conventional heparin (60 or 90 XaI u/kg b.w.) showed significant effects on the haemostatic plug formation time in the rabbit mesenteric microcirculation. These experiments confirm that low molecular weight heparins are potential antithrombotic drugs, which by intravenous administration have effects similar to those of standard heparin. The method of preparation seems to be of no or minor importance, at least if the molecular weight distributions of the products are similar.

Ultrasound properties of lung tissue and their measurements.

In-vitro measurements have been carried out for the group velocity and the attenuation, in dB/cm, in cow lung tissue. The velocity and the attenuation were measured both as a function of air content, from 32 to 68%, and as a function of frequency, from 10 to 800 KHz. The group velocity was determined from measurement of the phase difference between the transmitted and incident acoustic signal while the attenuation was measured from the insertion loss with correction for the water-lung interface transmission losses. The measured group velocities indicate only a small degree of dispersion, but a strong dependence on air content. The attenuation is very high and exhibits strong frequency dependence, but weak air content dependence.